Batf-Dependent Th17 cells act through IL23R pathway to promote prostate adenocarcinoma initiation and progression.

BACKGROUND: The role of Th17 cells in prostate cancer (PCa) is not fully understood. The transcription factor BATF controls the differentiation of Th17 cells. Mice deficient in Batf do not produce Th17 cells. METHODS: In this study, we aimed to characterize the role of Batf-dependent Th17 cells in PCa by crossbreeding Batf knockout (Batf-/-) mice with mice conditionally mutant for Pten. We found that Batf-/- mice had changes in the morphology of prostate epithelial cells compared to normal mice, and Batf-/- mice deficient in Pten (named Batf-) had smaller prostate size and developed fewer invasive prostate adenocarcinomas than Pten-deficient mice with Batf expression (named Batf+). The prostate tumors in Batf- mice showed reduced proliferation, increased apoptosis, decreased angiogenesis and inflammatory cell infiltration, and activation of NF-κB signaling. Moreover, Batf- mice showed significantly reduced IL-23/IL-23R signaling. In the prostate stroma of Batf- mice, IL-23R-positive cells were decreased considerably compared to Batf+ mice. Splenocytes and prostate tissues from Batf- mice cultured under Th17 differentiation conditions expressed reduced IL-23/IL-23R than cultured cells from Batf+ mice. Anti-IL23p19 antibody treatment of Pten-deficient mice reduced prostate tumors and angiogenesis compared to control IgG-treated mice. In human prostate tumors, BATF mRNA level was positively correlated with IL23A and IL-23R but not RORC. CONCLUSION: Our novel findings underscore the crucial role of IL-23/IL23R signaling in mediating the function of Batf-dependent Th17 cells, thereby promoting PCa initiation and progression. This highlights the Batf-IL-23R axis as a promising target for the development of innovative strategies for PCa prevention and treatment.

SCFFBXW11 Complex Targets Interleukin-17 Receptor A for Ubiquitin-Proteasome-Mediated Degradation.

Interleukin-17 (IL-17) is a pro-inflammatory cytokine that participates in innate and adaptive immune responses and plays an important role in host defense, autoimmune diseases, tissue regeneration, metabolic regulation, and tumor progression. Post-translational modifications (PTMs) are crucial for protein function, stability, cellular localization, cellular transduction, and cell death. However, PTMs of IL-17 receptor A (IL-17RA) have not been investigated. Here, we show that human IL-17RA was targeted by F-box and WD repeat domain-containing 11 (FBXW11) for ubiquitination, followed by proteasome-mediated degradation. We used bioinformatics tools and biochemical techniques to determine that FBXW11 ubiquitinated IL-17RA through a lysine 27-linked polyubiquitin chain, targeting IL-17RA for proteasomal degradation. Domain 665-804 of IL-17RA was critical for interaction with FBXW11 and subsequent ubiquitination. Our study demonstrates that FBXW11 regulates IL-17 signaling pathways at the IL-17RA level.

Case report: Rubella virus-induced cutaneous granulomas in a girl with atypical SCID caused by DCLRE1C gene mutations.

Here, we report a case of rubella virus-induced granulomatous dermatitis in a young girl with immunodeficiency caused by DCLRE1C gene mutations. The patient was a 6-year-old girl who presented with multiple erythematous plaques on the face and limbs. Biopsies of the lesions revealed tuberculoid necrotizing granulomas. No pathogens could be identified on extensive special stains, tissue cultures, or PCR-based microbiology assays. Metagenomic next-generation sequencing analysis revealed the rubella virus. Underlying atypical severe combined immunodeficiency was recognized based on the patient's history of repetitive infections since birth, low T-cell, B-cell, and NK cell counts, and abnormal immunoglobulins and complements. Whole-exome sequencing revealed the genetic abnormality of the atypical severe combined immunodeficiency (SCID), and compound heterozygous mutations of the DCLRE1C gene were detected. This report highlights the diagnostic values of metagenomic next-generation sequencing in identifying rare pathogens causing cutaneous granulomas in patients with atypical SCID.

Defect of IL17 Signaling, but Not Centrinone, Inhibits the Development of Psoriasis and Skin Papilloma in Mouse Models.

Patients with psoriasis tend to develop skin cancer, and the hyperproliferation of the epidermis is a histopathological hallmark of both psoriasis and cutaneous squamous cell carcinoma (SCC), indicating that they may share pathogenic mechanisms. Interleukin-17 (IL17) stimulates the proliferation of the epidermis, leading to psoriasis. Overexpression of Polo-like kinase 4 (PLK4), which controls centriole duplication, has been identified in SCC, which also shows the hyperproliferation of keratinocytes. To investigate the cooperation between IL17 signaling and centriole duplication in epidermal proliferation, we established psoriasis and skin papilloma models in wild type (WT), IL17 receptor A (T779A) knockin (Il17ra(T779A)-KI), and IL17 receptor C knockout (Il17rc-KO) mouse strains. Bioinformatics, Western blot, immunohistochemical staining, colony formation, and real-time PCR were used to determine the effect of IL17 signaling and centrinone on epithelial proliferation. In the psoriasis model, compared to WT and Il17ra(T779A)-KI, Il17rc-KO dramatically suppressed epidermal thickening. The proliferation of keratinocytes significantly decreased in this order from WT to Il17ra(T779A)-KI and Il17rc-KO mice. In the skin papilloma model, Il17ra(T779A)-KI significantly decreased tumor burden compared to the WT, while Il17rc-KO abolished papilloma development. However, centrinone, a selective inhibitor of PLK4, did not affect skin lesion formation in either model. Our data demonstrated that Il17ra(T779A)-KI and Il17rc-KO prevent the development of psoriasis and tumorigenesis in the skin, while the topical administration of centrinone does not have any effect.

A Novel Controlled PTEN-Knockout Mouse Model for Prostate Cancer Study.

Prostate cancer (PCa) is associated with advanced age, but how age contributes to prostate carcinogenesis remains unknown. The prostate-specific Pten conditional knockout mouse model closely imitates human PCa initiation and progression. To better understand how age impacts PCa in an experimental model, we have generated a spatially and temporally controlled Pten-null PCa murine model at different ages (aged vs. non-aged) of adult mice. Here, we present a protocol to inject the Cre-expressing adenovirus with luciferin tag, intraductally, into the prostate anterior lobes of Pten-floxed mice; Pten-loss will be triggered post-Cre expression at different ages. In vivo imaging of luciferin signal following viral infection confirmed successful delivery of the virus and Cre activity. Immunohistochemical staining confirmed prostate epithelial-specific expression of Cre recombinase and the loss of Pten and activation of P-Akt, P-S6, and P-4E-BP1. The Cre-expression, Pten ablation, and activated PI3K/AKT/mTOR pathways were limited to the prostate epithelium. All mice developed prostatic epithelial hyperplasia within 4 weeks after Pten ablation and prostatic intraepithelial neoplasia (PIN) within 8 weeks post-Pten ablation. Some PINs had progressed to invasive adenocarcinoma at 8-16 weeks post-Pten ablation. Aged mice exhibited significantly accelerated PI3K/AKT/mTOR signaling and increased PCa onset and progression compared to young mice. The viral infection success rate is ∼80%. This model will be beneficial for investigations of cancer-related to aging.

Pembrolizumab-induced pseudoepitheliomatous eruption consistent with hypertrophic lichen planus.

Pembrolizumab, an anti-programmed cell death-1 (PD-1) antibody preparation, has been shown to induce various dermatologic adverse events which may present with delayed onset or even after discontinuation of therapy. We report a 78-year-old female patient with a stage II lung adenocarcinoma treated with pembrolizumab, who developed lichenoid eruptions and multiple cutaneous plaque/nodular eruptions as pseudoepitheliomatous hyperplasia, during and up to 2 months after discontinuation of pembrolizumab therapy. Multiple skin biopsies revealed epidermal hyperplasia with hyperkeratosis, hypergranulosis, diffuse to patchy lichenoid lymphocyte infiltrate with scattered eosinophils and neutrophils, confluent to scant dyskeratosis of the lower epidermis, minimal to overt invagination, and cystic proliferation of squamous epithelium to papillomatosis with hypergranulosis and keratosis. Overall, multiple patterns were present with similarities to lichenoid drug eruption, lichen planus, early invasive squamous cell carcinoma, early keratoacanthoma, and verruca. However, the findings ultimately supported a diagnosis of hypertrophic lichen planus. All the lesions resolved with oral prednisone, hydroxychloroquine, and topical triamcinolone acetonide ointment 0.1%. In summary, our case shows that pembrolizumab can induce lichenoid eruption with pseudoepitheliomatous hyperplasia, and these lesions can clinically and pathologically mimic early invasive squamous cell carcinomas or keratoacanthomas.

Prognostic Role of BRAFV600E Cellular Localization in Melanoma.

BACKGROUND: Approximately half of cutaneous melanoma tissues harbor BRAFV600E mutations, resulting in a constitutive activation of the mitogen-activated protein kinase (MAPK) pathway. Nuclear-cytoplasmic transport machinery is dysregulated in neoplastic cells and alters the key regulatory proteins that can lead to tumor progression and drug resistance. The significance of nuclear localization of BRAFV600E has not been fully understood. We examined the clinical significance of intracellular localization of BRAFV600E in cutaneous melanoma. STUDY DESIGN: Immunohistochemical analysis of BRAFV600E was performed on formalin-fixed, paraffin-embedded specimens of cutaneous melanoma (n = 91). Staining intensity was graded in a blinded manner. Correlations to clinical factors were analyzed by Fisher's exact test and 2-tailed t-test. Localization of BRAFV600E was determined in melanoma cells, and we investigated their resistance to BRAFV600E-specific inhibitor according to nuclear localization in both in vitro and in vivo models. RESULTS: We included 91 patients, of whom 32% (29 of 91) had cytoplasmic BRAFV600E. Nuclear BRAFV600E was observed in 30% (27 of 91). Overall, BRAFV600E expression correlated with TNM stage (p = 0.011), mitotic activity (p = 0.010), and ulceration (p = 0.045). Nuclear BRAFV600E expression correlated with overall clinical stage (p < 0.001), tumor size (p < 0.001), regional lymph node (p < 0.017), depth of invasion (p = 0.005), Clark level (p < 0.001), mitotic activity (p < 0.001), ulceration (p < 0.001), and margin status (p = 0.017). On a cellular level, BRAFV600E was identified in the nucleus, and its translocation was serum dependent. Our in vitro and in vivo data revealed sequestration of BRAFV600E in the cytosol-sensitized resistant cells to vemurafenib; nuclear retention of BRAFV600E was associated with aggressiveness and drug resistance. CONCLUSIONS: Nuclear localization of BRAFV600E is associated with melanoma aggressiveness. Further multi-institutional studies are warranted to confirm the clinical relevance of nuclear localization of BRAFV600E.

PD-1, PD-L1 and PD-L2 expression in mouse prostate cancer.

Programmed cell death protein 1 (PD-1) and its ligands PD-L1 and PD-L2 play critical roles in maintaining an immunosuppressive tumor microenvironment. The purpose of the present study was to assess expression of PD-1, PD-L1, and PD-L2 in mouse prostate tumors. A total of 33 mouse prostate tumors derived from Pten-null mice were examined using immunohistochemical staining for PD-1, PD-L1, and PD-L2. The animals were either with interleukin-17 receptor c (Il-17rc) wild-type or knockout genotype, or fed with regular diet or high-fat diet to 30 weeks of age. We found that Il-17rc wild-type mouse prostate tumors had significantly higher levels of PD-1, PD-L1, and PD-L2 than Il-17rc knockout mouse prostate tumors. High-fat diet-induced obese mice had significantly higher levels of PD-1, PD-L1, and PD-L2 in their prostate tumors than lean mice fed with regular diet. Increased expression of PD-1, PD-L1, and PD-L2 was associated with increased number of invasive prostate tumors formed in the Il-17rc wild-type and obese mice compared to the Il-17rc knockout and lean mice, respectively. Our findings suggest that expression of PD-1, PD-L1, and PD-L2 may enhance development of mouse prostate cancer through creating an immunosuppressive tumor microenvironment.

Hyperinsulinemia enhances interleukin-17-induced inflammation to promote prostate cancer development in obese mice through inhibiting glycogen synthase kinase 3-mediated phosphorylation and degradation of interleukin-17 receptor.

Interleukin-17 (IL-17) plays important roles in inflammation, autoimmune diseases, and some cancers. Obese people are in a chronic inflammatory state with increased serum levels of IL-17, insulin, and insulin-like growth factor 1 (IGF1). How these factors contribute to the chronic inflammatory status that promotes development of aggressive prostate cancer in obese men is largely unknown. We found that, in obese mice, hyperinsulinemia enhanced IL-17-induced expression of downstream proinflammatory genes with increased levels of IL-17 receptor A (IL-17RA), resulting in development of more invasive prostate cancer. Glycogen synthase kinase 3 (GSK3) constitutively bound to and phosphorylated IL-17RA at T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA, thus inhibiting IL-17-mediated inflammation. IL-17RA phosphorylation was reduced, while the IL-17RA levels were increased in the proliferative human prostate cancer cells compared to the normal cells. Insulin and IGF1 enhanced IL-17-induced inflammatory responses through suppressing GSK3, which was shown in the cultured cell lines in vitro and obese mouse models of prostate cancer in vivo. These findings reveal a mechanism underlying the intensified inflammation in obesity and obesity-associated development of aggressive prostate cancer, suggesting that targeting GSK3 may be a potential therapeutic approach to suppress IL-17-mediated inflammation in the prevention and treatment of prostate cancer, particularly in obese men.

20(S)-protopanaxadiol inhibition of progression and growth of castration-resistant prostate cancer.

Castration-resistant progression of prostate cancer after androgen deprivation therapies remains the most critical challenge in the clinical management of prostate cancer. Resurgent androgen receptor (AR) activity is an established driver of castration-resistant progression, and upregulation of the full-length AR (AR-FL) and constitutively-active AR splice variants (AR-Vs) has been implicated to contribute to the resurgent AR activity. We reported previously that ginsenoside 20(S)-protopanaxadiol-aglycone (PPD) can reduce the abundance of both AR-FL and AR-Vs. In the present study, we further showed that the effect of PPD on AR expression and target genes was independent of androgen. PPD treatment resulted in a suppression of ligand-independent AR transactivation. Moreover, PPD delayed castration-resistant regrowth of LNCaP xenograft tumors after androgen deprivation and inhibited the growth of castration-resistant 22Rv1 xenograft tumors with endogenous expression of AR-FL and AR-Vs. This was accompanied by a decline in serum prostate-specific antigen levels as well as a decrease in AR levels and mitoses in the tumors. Notably, the 22Rv1 xenograft tumors were resistant to growth inhibition by the next-generation anti-androgen enzalutamide. The present study represents the first to show the preclinical efficacy of PPD in inhibiting castration-resistant progression and growth of prostate cancer. The findings provide a rationale for further developing PPD or its analogues for prostate cancer therapy.

Interleukin-17 promotes development of castration-resistant prostate cancer potentially through creating an immunotolerant and pro-angiogenic tumor microenvironment.

BACKGROUND: Interleukin-17 (IL-17) has been demonstrated to promote formation and growth of hormone-naïve prostate adenocarcinoma in mice. IL-17's role in development of castration-resistant prostate cancer is unknown. In the present study, we investigated IL-17's role in castration-resistant prostate cancer in a mouse model. METHODS: IL-17 receptor C (IL-17RC) deficient mice were interbred with Pten conditional mutant mice to produce RC(+) mice that maintained IL-17RC expression and RC(-) mice that were IL-17RC deficient. Male RC(+) and RC(-) mice were Pten-null and were castrated at 16 weeks of age when invasive prostate cancer had already formed. At 30 weeks of age, all male mice were analyzed for the prostate phenotypes. RESULTS: RC(-) mice displayed prostates that were smaller than RC(+) mice. Approximately 23% of prostatic glands in RC(-) mice, in contrast to 65% of prostatic glands in RC(+) mice, developed invasive adenocarcinomas. Compared to castrate RC(+) mice, castrate RC(-) mouse prostate had lower rates of cellular proliferation and higher rates of apoptosis as well as lower levels of MMP7, YBX1, MTA1, and UBE2C proteins. In addition, castrate RC(-) mouse prostate had less angiogenesis, which was associated with decreased levels of COX-2 and VEGF. Moreover, castrate RC(-) mouse prostate had fewer inflammatory cells including lymphocytes, myeloid-derived suppressor cells, and macrophages. CONCLUSIONS: Taken together, our findings suggest that IL-17 promotes development of invasive prostate adenocarcinomas under castrate conditions, potentially through creating an immunotolerant and pro-angiogenic tumor microenvironment.

Composite lymphoid neoplasm of B-cell and T-cell origins: a pathologic study of 14 cases.

We retrospectively analyzed 14 composite lymphoma/lymphoid neoplasms (CL) of B-cell/T-cell origins. These consisted of a spectrum of T-cell neoplasms in combination with different B-cell lymphomas/leukemias, with peripheral T-cell lymphoma and diffuse large B-cell lymphoma encountered most frequently for each respective neoplastic lineage. Histopathologic evaluation demonstrated 6 patterns of neoplastic distribution, including zone, inverted zone, diffuse mixed, regional/nodular mixed, compartmental, and segmental distributions. Four of 9 cases studied were positive for Epstein-Barr virus, all with a mixed pattern, suggesting that this pattern may predict an Epstein-Barr virus association. None of 14 cases was considered CL at the initial histologic evaluation. Only 6 (46.2%) of 13 cases had coexisting B-cell/T-cell neoplasms highlighted by immunohistochemistry, and the other 7 (53.8%) cases had 1 or both of the neoplastic components hidden. Flow cytometry detected both neoplastic lineages in 4 (44%) but failed to detect a clonal B-cell population in 4 (44%) and missed neoplastic T cells in 1 (11.1%) of 9 cases. Molecular testing detected clonal rearrangement of IGH/K gene in 11 (84.6%) of 13 cases, and clonal rearrangement of the TCRG/B gene in 13 (92.9%) of 14 cases, including 8 with identical amplicons detected in separate samples. CLs of B-cell/T-cell origin are heterogeneous in subtype combination and topographic pattern, often with one of the components histologically occult. A multidisciplinary approach is emphasized to establish a definitive diagnosis in these challenging cases.

Composite lymphoma of mycosis fungoides and cutaneous small B-cell lymphoma in a 73-year-old male patient.

Composite lymphoma of T-cell and B-cell type is uncommon, and the one occurring primarily on skin is extremely rare. Herein, we report a unique case of composite lymphoma of mycosis fungoides and cutaneous small B-cell lymphoma in a 73-year-old male patient. The patient presented with multiple erythematous patches, plaques, and nodules on the upper arms, scalp, and trunk. Four punch biopsies of arm and scalp lesions demonstrated lymphoid infiltrate in superficial to deep dermis with a characteristic zone distribution of T-cell and B-cell components. T cells were distributed in papillary and perifollicular dermis and displayed a larger size with convoluted nuclei, whereas B cells were small sized, assuming nodular infiltrate in mid-deep dermis with coexpression of CD5. Molecular test detected clonal rearrangement of both TCRG and IGH/K genes with identical amplicons for each gene in all 4 biopsies. Clinical staging revealed no extracutaneous lesions. A multidisplinary approach is emphasized to establish a definitive diagnosis.

Cutaneous mercury granuloma: a case report.

Cutaneous mercury (Hg) granuloma is a rare disorder caused by the traumatic introduction of elemental Hg into skin or soft tissue. Typically, cutaneous elemental Hg deposits cause limited systemic effects. Prominent systemic toxicity may, however, occasionally occur. Herein we report a case of cutaneous Hg granuloma resulting in chronic painful local wounds and systemic toxicity in the form of abdominal pain, visual disturbances, and psychiatric abnormalities. The related literature also is reviewed.

Silicone migration and granuloma formation.

The use of liquid injectable silicone for soft tissue augmentation is a controversial practice within the medical community. Injectable silicone has been illegally obtained, adulterated, and abused by nonmedical practitioners for the last five decades. Injection of silicone can result in catastrophic consequences including death, when grossly abused. Opponents of this practice cite the many serious adverse events that have occurred with its use both legally and illegally. Proponents argue that employment of a stringent regimen of use as well as a highly purified medical grade product allow for a safe utilization of the material. Both sides agree that this practice calls for a high degree of knowledge and technical skill. A continued evaluation of the long-term safety of this material is necessary before a consensus can be reached. Herein, we report a case of illegal administration of injectable silicone resulting in product migration accompanied by a granulomatous response. Further, the literature that both supports and refutes the practice of silicone injection is reviewed.

Calcium signaling and T-type calcium channels in cancer cell cycling.

Regulation of intracellular calcium is an important signaling mechanism for cell proliferation in both normal and cancerous cells. In normal epithelial cells, free calcium concentration is essential for cells to enter and accomplish the S phase and the M phase of the cell cycle. In contrast, cancerous cells can pass these phases of the cell cycle with much lower cytoplasmic free calcium concentrations, indicating an alternative mechanism has developed for fulfilling the intracellular calcium requirement for an increased rate of DNA synthesis and mitosis of fast replicating cancerous cells. The detailed mechanism underlying the altered calcium loading pathway remains unclear; however, there is a growing body of evidence that suggests the T-type Ca(2+) channel is abnormally expressed in cancerous cells and that blockade of these channels may reduce cell proliferation in addition to inducing apoptosis. Recent studies also show that the expression of T-type Ca(2+) channels in breast cancer cells is proliferation state dependent, i.e. the channels are expressed at higher levels during the fast-replication period, and once the cells are in a non-proliferation state, expression of this channel is minimal. Therefore, selectively blocking calcium entry into cancerous cells may be a valuable approach for preventing tumor growth. Since T-type Ca(2+) channels are not expressed in epithelial cells, selective T-type Ca(2+) channel blockers may be useful in the treatment of certain types of cancers.

Juvenile chondrodermatitis nodularis helicis: a case report and literature review.

Chondrodermatitis nodularis helicis (CNH) is a disorder that affects adults. Only one case of juvenile CNH has been reported, in an 8-year-old child who suffered from dermatomyositis. We report another child with juvenile CNH who was not afflicted with dermatomyositis or other systemic disorders. The clinical and histologic evaluations demonstrated CNH on the helix of the right ear in a 16-year-old Caucasian girl who was otherwise healthy. Serologic analysis ruled out an underlying autoimmune disorder. We conclude that juvenile CNH is extremely rare and may occur in patients without dermatomyositis or other systemic disorders.

Monophasic sarcomatoid carcinoma of the scalp: a case mimicking inflammatory myofibroblastic tumor and a review of cutaneous spindle cell tumors with myofibroblastic differentiation.

BACKGROUND: The evaluation of malignant cutaneous spindle cell tumors is challenged by a diagnostic differential that comprises neoplasms of diverse histogenesis, and a broad immunohistochemical panel may confound the diagnosis when the results suggest multiple lines of differentiation, such as with a combined myofibroblastic and epithelial phenotype. METHODS: We report the case of a solitary scalp nodule that quickly became locally metastatic. A comprehensive panel of immunohistochemistry markers and electron microscopy was evaluated to determine the differentiation of the spindle cells. RESULTS: The tumor, consisting of wavy and slender spindle cells with predominantly bland nuclei, showed immunoreactivity to vimentin, smooth muscle actin, and muscle-specific actin. AE1/AE3, CK5/6, and MNF-116 antibodies were weakly positive in rare cells. However, 34betaE12 showed diffuse positivity in the spindle cell population, thus supporting the diagnosis of a sarcomatoid carcinoma with myofibroblastic differentiation. CONCLUSIONS: The use of 34betaE12 is essential for the evaluation of myofibroblastic spindle cell tumors with rare cytokeratin reactivity. However, even with immunohistochemical and electron microscopic studies, the diagnosis of spindle cell tumors can be confounded by the multiplicity of nosologic equivalents, such as carcinosarcoma, spindle cell carcinoma, and metaplastic carcinoma. The nomenclature of these spindle cell tumors is discussed.